SUBSTITUTED IMIDAZO[1,5-a]PYRAZINES AS CGRP RECEPTOR ANTAGONISTS

ABSTRACT

The disclosure generally relates to the novel compounds of formula I, including pharmaceutically acceptable salts, which arc CGRP-receptor antagonists. The disclosure also relates to pharmaceutical compositions and methods for using the compounds in the treatment of CGRP related disorders including migraine headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, and chronic obstructive pulmonary disease (COPD).

BACKGROUND OF THE INVENTION

The disclosure generally relates to the novel compounds of formula I,including pharmaceutically acceptable salts, which are CGRP-receptorantagonists. The disclosure also relates to pharmaceutical compositionsand methods for using the compounds in the treatment of CGRP relateddisorders including migraine headaches, neurogenic vasodilation,neurogenic inflammation, thermal injury, circulatory shock, flushingassociated with menopause, airway inflammatory diseases such as asthma,and chronic obstructive pulmonary disease (COPD).

Calcitonin gene-related peptide (CGRP) is a naturally occurring37-amino-acid peptide first identified in 1982 (Amara, S. G. et al,Science 1982, 298, 240-244). Two forms of the peptide are expressed(αCGRP and βCGRP) which differ by one and three amino acids in rats andhumans, respectively. The peptide is widely distributed in both theperipheral (PNS) and central nervous system (CNS), principally localizedin sensory afferent and central neurons, and displays a number ofbiological effects, including vasodilation.

When released from the cell, CGR.P binds to specific cell surface Gprotein-coupled receptors and exerts its biological action predominantlyby activation of intracellular adenylate cyclase (Poyncr, D. R. et al,Br J Pharmacol 1992, 105, 441-7; Van Valen, F. et al, Neurosci. Lett1990, 119, 195-8.). Two classes of CGRP receptors, CGRP1 and CGRP2, havebeen proposed based on the antagonist properties of the peptide fragmentCGRP(8-37) and the ability of linear analogues of CGRP to activate CGRP2receptors (Juaneda, C. et al. TiPS 2000, 21, 432-438). However, there islack of molecular evidence for the CGRP2 receptor (Brain, S. D. et al,TiPS 2002, 23, 51-53). The CGRP1 receptor has three components: (i) a 7transmembrane calcitonin receptor-like receptor (CRLR); (ii) the singletransmembrane receptor activity modifying protein type one (RAMP1); and(iii) the intracellular receptor component protein (RCP) (Evans B. N. etal., J Biol Chem. 2000, 275, 31438-43). RAMP1 is required for transportof CRLR to the plasma membrane and for ligand binding to theCGRP-receptor (McLatchie, L. M. et al, Nature 1998, 393, 333-339). RCPis required for signal transduction (Evans B. N. et al., J Biol Chem.2000, 275, 31438-43). There are known species-specific differences inbinding of small molecule antagonists to the CGRP-receptor withtypically greater affinity seen for antagonism of the human receptorthan for other species (Brain, S. D. et al, TiPS 2002, 23, 51-53). Theamino acid sequence of RAMP 1 determines the species selectivity, inparticular, the amino acid residue Trp74 is responsible for thephenotype of the human receptor (Malice et al. J Biol Chem 2002, 277,14294-8).

Inhibitors at the receptor level to CGRP are postulated to be useful inpathophysiologic conditions where excessive CGRP receptor activation hasoccurred. Some of these include neurogenic vasodilation, neurogenicinflammation, migraine, cluster headache and other headaches, thermalinjury, circulatory shock, menopausal flushing, and asthma. CGRPreceptor activation has been implicated in the pathogenesis of migraineheadache (Edvinsson L. CNS Drugs 2001;15(10):745-53; Williamson, D. J.Microsc. Res. Tech. 2001, 53, 167-178.; Grant, A. D. Brit. J. Pharmacol.2002, 135, 356-362.). Serum levels of CGRP are elevated during migraine(Goadsby PJ, et al. Ann Neurol 1990;28:183-7) and treatment withanti-migraine drugs returns CGRP levels to normal coincident withalleviation of headache (Gallai V. et al. Cephalalgia 1995;15: 384-90).Migraineurs exhibit elevated basal CGRP levels compared to controls(Ashina M, et al., Pain 2000, 86(1-2):133-8.2000). Intravenous CGRPinfusion produces lasting headache in migraineurs (Lassen L H, et al.Cephalalgia 2002 February; 22(1):54-61). Preclinical studies in dog andrat report that systemic CGRP blockade with the peptide antagonistCGRP(8-37) does not alter resting systemic hemodynamics nor regionalblood flow (Shen, Y-T. et al, J Pharmacol Exp Ther 2001, 298, 551-8).Thus, CGRP-receptor antagonists may present a novel treatment formigraine that avoids the cardiovascular liabilities of activevasoconstriction associated with non-selective 5-HT1B/1D agonists,‘triptans’ (e.g., sumatriptan). CGRP antagonists have shown efficacy inhuman clinical trials. See Davis C D, Xu C. Curr Top Med Chem. 20088(16):1468-79; Benemei S, Nicoletti P, Capone J G, Geppetti P. Curr OpinPharmacol. 2009 9(1):9-14. Epub 2009 Jan. 20; Ho T W, Ferrari M D,Dodick D W, Galet V, Kost J, Fan X, Leibensperger H, Froman. S, AssaidC, Lines C, Koppen H, Winner P K. Lancet. 2008 372:2115. Epub 2008 Nov.25; Ho T W, Mannix L K, Fan X, Assaid C, Furtek C, Jones C J, Lines C R,Rapoport A M; Neurology 2008 70:1304. Epub 2007 Oct. 3.

CGRP receptor antagonists have been disclosed. See U.S. Pat. No.7,569,578 and US patent application publication 20100324023.

DESCRIPTION OF THE INVENTION

The invention encompasses a series of CGRP antagonist compoundsincluding pharmaceutically acceptable salts, compositions, methods ofmaking them, and methods of using them in therapeutic treatment.

One aspect of the invention is a compound of formula I

where:

-   R¹ is hydrogen, alkyl, cycloalkyl, or (Ar²)alkyl;-   R² is piperidinyl substituted with 1 substituent selected from the    group consisting of

-   R³ is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or    haloalkoxy;-   R⁴ is hydrogen, halo, cyano, alkyl, h.aloalkyl, alkoxy, or    haloalkoxy;-   Ar¹ is indazolyl. substituted with 0-1 substituents selected from    the group consisting of halo, alkyl, and haloalkyl;-   Ar² is phenyl substituted with 0-3 substituents selected from the    group consisting of halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;    and-   X is O, CH₂, or NH;-   or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹ ishydrogen, alkyl, cycloalkyl, or (Ar²)alkyl; R² is piperidinylsubstituted with 1 substituent selected from the group consisting of

-   R³ is hydrogen; R⁴ is hydrogen; Ar¹ is indazolyl substituted with 1    alkyl substituent;-   Ar² is phenyl; and X is O; or a pharmaceutically acceptable salt    thereof.

Another aspect of the invention is a compound of formula 1 where R¹ ishydrogen, ethyl, cyclohexyl, or benzyl; R² is piperidinyl substitutedwith 1

substituent; R³ is hydrogen; R⁴ is hydrogen; Ar¹ is indazolylsubstituted with 1 methyl substituent; Ar² is phenyl; and X is O; or apharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹ ishydrogen, ethyl, cyclohexyl, or benzyl.

Another aspect of the invention is a compound of formula I where R² ispiperidinyl 4-substituted with 1 substituent selected from the groupconsisting of

Another aspect of the invention is a compound of formula I where Ar¹ isindazolyl substituted with 1 alkyl substituent.

Another aspect of the invention is a compound of formula I where Ar² isphenyl.

Another aspect of the invention is a compound of formula I where X is O.

Another aspect of the invention is a compound of formula I with thedesignated stereochemistry.

The scope of any instance of a variable, including R¹, R², R³, R⁴, Ar¹,Ar², and X, can be used independently with the scope of any otherinstance of a variable substituent. As such, the invention includescombinations of the different aspects.

Unless specified otherwise, these terms have the following meanings.“Halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” and“haloalkoxy” include all halogenated isomers from monohalo to perhalo.“Alkyl” means a straight or branched alkyl group composed of 1 to 6carbons. “Alkenyl” means a straight or branched alkyl group composed of2 to 6 carbons with at least one double bond. “Alkynyl” means a straightor branched alkyl group composed of 2 to 6 carbons with at least onetriple bond. “Cycloalkyl” means a monocyclic ring system composed of 3to 7 carbons. Terms with a hydrocarbon moiety (e.g. alkoxy) includestraight and branched isomers for the hydrocarbon portion. “Aryl” meansa monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12carbon atoms, or a bicyclic fused ring system wherein one or both of therings is a phenyl group. Bicyclic fused ring systems consist of a phenylgroup fused to a four-to six-membered aromatic or non-aromaticcarbocyclic ring. Representative examples of aryl groups include, butare not limited to, indanyl, indanyl, naphthyl, phenyl, andtetrahydronaphthyl. “Heteroaryl” means a 5 to 7 membered monocyclic or 8to 11 membered bicyclic aromatic ring system with 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Parentheticand multiparenthetic terms arc intended to clarify bonding relationshipsto those skilled in the art. For example, a term such as ((R)alkyl)means an alkyl substituent further substituted with the substituent R.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some compounds of the invention may exist in stereoisomeric forms, oneexample of which is shown below. The invention includes allstereoisomeric and tautomeric forms of the compounds.

The invention is intended to include all isotopes of atoms occurring inthe present compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. By way of general example andwithout limitation, isotopes of hydrogen include deuterium and tritium.Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compoundsof the invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed herein, using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent otherwise employed. Such compounds mayhave a variety of potential uses, for example as standards and reagentsin determining biological activity. In the case of stable isotopes, suchcompounds may have the potential to favorably modify biological,pharmacological, or pharmacokinetic properties.

Synthetic Methods

The compounds may be made by methods known in the art including thosedescribed below and including variations within the skill of the art.Some reagents and intermediates are known in the art. Other reagents andintermediates can be made by methods known in the art using readilyavailable materials. The following methods are for illustrative purposesand are not intended to limit the scope of the invention. It will beappreciated by those skilled in the art that there are a number ofmethods available for the synthesis of these compounds and that theirsynthesis is not limited to the methods provided in the followingexamples. Variations of the compounds and the procedures to make themwhich are not illustrated are within the skill of the art. The variablesdescribing general structural formulas and features in the syntheticschemes are distinct from and should not be confused with the variablesin the claims or the rest of the specification. These variables aremeant only to illustrate how to make some of the compounds of theinvention.

Some Formula I compounds can be synthesized through the followinggeneral schemes.

Biological Methods In Vitro Pharmacology.

Tissue Culture. SK-N-MC cells were grown at 37° C. in 5% CO₂ as amonolayer in medium consisting of MEM with Earle's salts and L-glutamine(Invitrogen) supplemented with 10% fetal bovine scrum (Invitrogen).

Membrane Preparation. Crude membranes were prepared from SK-N-MC cellsexpressing CGRP receptors. The cells were rinsed twice withphosphate-buffered saline (155 mM NaCl, 3.3 mM Na₂HPO₄, 1.1 mM KH₂PO₄,pH 7.4), and incubated for 5-10 min. at 4° C. in hypotonic lysis bufferconsisting of 10 mM Tris (pH 7.4) and 5 mM EDTA. The cells weretransferred from plates to polypropylene tubes (16×100 mm) andhomogenized using a polytron. Homogenates were centrifuged at 32,000 ×gfor 30 min. The pellets were resuspended in cold hypotonic lysis bufferwith 0.1% mammalian protease inhibitor cocktail (Sigma) and assayed forprotein concentration. The SK-N-MC homogenate was aliquoted and storedat −80° C.

Radioligand Binding Assay. The compounds of invention were solubilizedand carried through serial dilutions using 100% DMSO. Aliquots from thecompound serial dilutions were further diluted 25 fold into assay buffer(50 mM Tris-Cl pH 7.5, 5 mM MgCl₂, 0.005% Triton X-100) and transferred(volume 50 μl) into 96 well assay plates. [¹²⁵I]-CGRP (GE Healthcare orPerkin-Elmer) was diluted to 72 pM in assay buffer and a volume of 50 μlwas added to each well. SK-N-MC membranes were thawed, diluted in assaybuffer with fresh 0.1% mammalian protease inhibitor cocktail (Sigma),and re-homogenized. SK-N-MC homogenate (7 μg/well) was added in a volumeof 100 μl. The assay plates were then incubated at room temperature for2 h. Assays were stopped by addition of excess cold wash buffer (50 mMTris-Cl pH 7.5, 0.1% BSA) immediately followed by filtration over glassfiber filters (Whatman GF/B) previously soaked in 0.5% PEI. Non-specificbinding was defined with 1 μM beta-CGRP (Bachem). Protein boundradioactivity was determined using a gamma or scintillation counter. Theresulting data was analyzed using a four parameter competitive bindingequation (XLfit v2.0) and the IC₅₀ was defined as the concentration of acompound of invention required to displace 50% of radioligand binding.Final assay concentration of [¹²⁵I]-CGRP was 18 pM. The mean Kd for[¹²⁵I]-CGRP is 25.4 pM. All compounds of invention were evaluated in atleast two separate experiments. See table 1 for data summary.

TABLE 1 Human CGRP Binding Human CGRP Receptor Example IC₅₀ (nM) 1 0.262 1.70 3 2.95 4 0.22

Pharmaceutical Compositions and Methods of Treatment

The compounds of Formula I inhibit the CGRP receptor. As such, they areuseful for treating conditions or disorders associated with aberrantCGRP levels or where modulating CGRP levels may have therapeuticbenefit.

Accordingly, another aspect of the invention is a pharmaceuticalcomposition comprising a compound of Formula I with a pharmaceuticallyacceptable adjuvant, carrier, or diluent.

Compounds are generally given as pharmaceutical compositions comprisedof a therapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt, and a pharmaceutically acceptablecarrier and may contain conventional exipients. A therapeuticallyeffective amount is the amount needed to provide a meaningful patientbenefit as determined by practitioners in that art. Pharmaceuticallyacceptable carriers are those conventionally known carriers havingacceptable safety profiles. Compositions encompass all common solid andliquid forms including capsules, tablets, losenges, and powders as wellas liquid suspensions, syrups, elixers, and solutions. Solidcompositions may by formed in timed or sustained released formulations.Compositions are made using common formulation techniques andconventional excipients (such as binding and wetting agents) andvehicles (such as water and alcohols).

Solid compositions are normally formulated in dosage units providingfrom about 1 to about 1000 mg of the active ingredient per dose. Someexamples of solid dosage units are 0.1 mg, 1 mg, 10 mg, 100 mg, 500 mg,and 1000 mg. Liquid compositions are generally in a unit dosage range of1-100 mg/mL. Some examples of liquid dosage units are 0.1 mg/mL, 1mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.

The invention encompasses all conventional modes of administrationincluding oral, parenteral, intranasal, sublingual, and transdermalmethods. Typically, the daily dose will be 0.01-100 mg/kg body weightdaily. Generally, more compound is required orally and lessparenterally. The specific dosing regime, however, should be determinedby a physician using sound medical judgement.

Inhibitors at the receptor level to CGRP are postulated to be useful inpathophysiologic conditions where excessive CGRP receptor activation hasoccurred.

Some of these include neurogenic vasodilation, neurogenic inflammation,migraine, cluster headache and other headaches, thermal injury,circulatory shock, menopausal flushing, and asthma. CGRP receptoractivation has been implicated in the pathogenesis of migraine headache(Edvinsson L. CNS Drugs 2001, 15(10),745-53; Williamson, D. J. Microsc.Res. Tech. 2001, 53, 167-178.; Grant, A. D. Brit. J. Pharmacol. 2002,135, 356-362.). Serum levels of CGRP are elevated during migraine(Goadsby P. J. et al. Ann. Neurol. 1990, 28, 183-7) and treatment withanti-migraine drugs returns CGRP levels to normal coincident withalleviation of headache (Gallai V. et al. Cephalalgia 1995, 15, 384-90).Migraineurs exhibit elevated basal CGRP levels compared to controls(Ashina M. et al., Pain 2000, 86(1-2), 133-8). Intravenous CGRP infusionproduces lasting headache in migraineurs (Lassen L. H. et al.Cephalalgia. 2002, 22(1), 54-61). Preclinical studies in dog and ratreport that systemic CGRP blockade with the peptide antagonistCGRP(8-37) does not alter resting systemic hemodynamics nor regionalblood flow (Shen, Y-T. et al. J. Pharmacol. Exp. Ther. 2001, 298,551-8). Thus, CGRP-receptor antagonists may present a novel treatmentfor migraine that avoids the cardiovascular liabilities of activevasoconstriction associated with non-selective 5-HT1B/1D agonists,“triptans” (e.g., sumatriptan).

Another aspect of the invention is a method of inhibiting the CGRPreceptor comprising contacting the CGRP receptor with a compound offormula I or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method for treating conditionsassociated with aberrant levels of CGRP comprising the administration ofa therapeutically effective amount of a compound of formula Ito apatient.

Another aspect of the invention is the use of a compound of formula I inthe manufacture of a medicament for the treatment of conditions relatedto aberrant levels of CGRP.

Another aspect of the invention is a method of treating migraine orheadache.

Another aspect of the invention relates to a method of treatinginflammation (particularly neurogenic inflammation), pain, thermalinjury, circulatory shock, diabetes, Reynaud's syndrome, peripheralarterial insufficiency, subarachnoid/cranial hemorrhage, tumor growth,flushing associated with menopause and other conditions the treatment ofwhich can be effected by the antagonism of the CGRP receptor by theadministration of pharmaceutical compositions comprising compounds ofFormula (I) as defined herein.

Another aspect of the invention relates to methods selected from thegroup consisting of (a) immune regulation in gut mucosa (b) protectiveeffect against cardiac anaphylactic injury (c) stimulating or preventinginterleukin-lb(IL-lb)-stimulation of bone resorption (d) modulatingexpression of NK1 receptors in spinal neurons and (e) airwayinflammatory diseases and chronic obstructive pulmonary diseaseincluding asthma. See (a) Calcitonin Receptor-Like Receptor Is Expressedon Gastrointestinal Immune Cells. Hagner, Stefanie; Knauer, Jens;Haberberger, Rainer; Goeke, Burkhard; Voigt, Karlheinz; McGregor, GerardPatrick. Institute of Physiology, Philipps University, Marburg, Germany.Digestion (2002), 66(4), 197-203; (b) Protective effects of calcitoningene-related peptide-mediated evodiamine on guinea-pig cardiacanaphylaxis. Rang, Wei-Qing; Du, Yan-Hua; Hu, Chang-Ping; Ye, Feng; Tan,Gui-Shan; Deng, Han-Wu; Li, Yuan-Jian. School of PharmaceuticalSciences, Department of Pharmacology, Central South University, Xiang-YaRoad 88, Changsha, Hunan, Naunyn-Schmiedeberg's Archives of Pharmacology(2003), 367(3), 306-311; (c) The experimental study on the effectcalcitonin gene-related peptide on bone resorption mediated byinterleukin-1. Lian, Kai; Du, Jingyuan; Rao, Zhenyu; Luo, Huaican.Department of Orthopedics, Xiehe Hospital, Tongji Medical. College,Huazhong University of Science and Technology, Wuhan, Peop. Rep. China.Journal of Tongji Medical University (2001), 21(4), 304-307, (d)Calcitonin gene-related Peptide regulates expression of neurokinin)receptors by rat spinal neurons. Seybold V S, McCarson K E, MermelsteinP G, Groth R D, Abrahams L G. J. Neurosci. 2003 23 (5): 1816-1824.epartment of Neuroscience, University of Minnesota, Minneapolis, Minn.55455, and Department of Pharmacology, Toxicology, and Therapeutics,University of Kansas Medical Center, Kansas City, Kans. 66160 (e)Attenuation of antigen-induced airway hyperresponsiveness inCGRP-deficient mice. Aoki-Nagase, Tomoko; Nagase, Takahide; Oh-Hashi,Yoshio; Shindo, Takayuki; Kurihara, Yukiko; Yamaguchi, Yasuhiro;Yamamoto, Hiroshi; Tomita, Tetsuji; Ohga, Eijiro; Nagai, Ryozo;Kurihara, Hiroki; Ouchi, Yasuyoshi. Department of Geriatric Medicine,Graduate School of Medicine, University of Tokyo, Tokyo, Japan. AmericanJournal of Physiology (2002), 283(5,Pt. 1), L963-L970; (f) Calcitoningene-related peptide as inflammatory mediator. Springer, Jochen;Geppetti, Pierangelo; Fischer, Axel; Groneberg, David A. ChariteCampus-Virchow, Department of Pediatric Pneumology and Immunology,Division of Allergy Research, Humboldt-University Berlin, Berlin,Germany. Pulmonary Pharmacology & Therapeutics (2003), 16(3), 121-130;and (g) Pharmacological targets for the inhibition of neurogenicinflammation. Helyes, Zsuzsanna; Pinter, Erika; Nemeth, Jozsef;Szolcsanyl, Janos. Department of Pharmacology and Pharmacotherapy,Faculty of Medicine, University of Pecs, Pecs, Hung. Current MedicinalChemistry: Anti-Inflammatory & Anti-Allergy Agents (2003), 2(2),191-218.

Another aspect of this invention relates to a method of treatment usingcombinations of Formula I compounds with one or more agents selectedfrom the group consisting of COX-2 inhibitors, NSAIDS, aspirin,acetaminophen, triptans, ergotamine and caffeine for the treatment ofmigraine.

“Migraine,” “headache,” and related terms are as understood by medicalpractitioners. Migraine encompasses all classes of migraine includingcommon, classic, cluster, fulgurating, hemiplegic, opthalmoplegic, andopthomalmic.

“Therapeutically effective” means there is a meaningful patient benefitas understood by medical practitioners.

“Patient” means a person who may benefit from treatment as determined bymedical practitioners.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The following experimental procedures describe the synthesis of someFormula I compounds. Standard chemistry conventions are used in the textunless otherwise noted. The experimental encompass reasonable variationsknown in the art. The following HPLC conditions may be used whereindicated.

Abbreviations used in the schemes generally follow conventions used inthe art. Chemical abbreviations used in the specification and examplesare defined as follows: “NaHMDS” for sodium bis(trimethylsilyl)amid.e;“DMF” for N,N-dimethylformamide; “MeOH” for methanol; “NBS” forN-bromosuccinimide; “Ar” for aryl; “TFA” for trifluoroacetic acid; “LAH”for lithium aluminum hydride; “BOC” for t-butoxycarbonyl, “DMSO” fordimethylsulfoxide; “h” for hours; “rt” for room temperature or retentiontime (context will dictate); “min” for minutes; “EtOAc” for ethylacetate; “THF” for tetrahydrofuran; “EDTA” forethylenediaminetetraacetic acid; “Et₂O” for diethyl ether; “DMAP” for4-dimethylaminopyridine; “DCE” for 1,2-dichloroethane; “ACN” foracetonitrile; “DME” for 1,2-dimethoxyethane; “HOBt” for1-hydroxybenzotriazole hydrate; “DIEA” for diisopropylethylamine, “Nf”for CF₃(CF₂)₃SO₂-; and “TMOF” for trimethylorthoformate.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“4” for microliter or microliters, “N” for normal, “M” for molar, “mmol”for millimole or millimoles, “min” for minute or minutes, “h” for houror hours, “rt” for room temperature, “RT” for retention time, “atm” foratmosphere, “psi” for pounds per square inch, “cone.” for concentrate,“sat” or “sat'd ” for saturated, “MW” for molecular weight, “mp” formelting point, “ce” for enantiomeric excess, “MS” or “Mass Spec” formass spectrometry, “ESI” for electrospray ionization mass spectroscopy,“HR” for high resolution, “HRMS” for high resolution mass spectrometry“LCMS” for liquid chromatography mass spectrometry, “HPLC” for highpressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC”or “tic” for thin layer chromatography, “NMR” for nuclear magneticresonance spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

Analytical HPLC method 1: Phenomenex 4.6×50 mm C18 10 um, A=90% H₂O/10%MeOH, B=90% MeOH/10% H₂O, Modifier 0.1% TFA, 0.00 min=0% B, 3.0 min=100%B, 4.0min=100% B, Flow rate=4 mL/min.

-   Analytical HPLC method 2: Phenomenex 4.6×50 mm C18 10 um, A=90%    H₂O/10% MeOH, B=90% MeOH/10% H₂O, Modifier 0.1% TFA, 0.00 min=0% B,    3.0 min=100% B, 3.0 min=100% B, Flow rate=4 mL/min.

Intermediate 1

Methyl 2-(1-benzylpiperidin-4-yl)acetate. Sodium hydride (60% in mineraloil, 10.55 g, 264 mmol) was washed with hexanes then suspended inN,N-dimethylformamide (200 mL). Mixture was cooled to 0° C. Trimethylphosphonoacetate (38.0 mL, 249 mmol) was added to the mixture dropwise.The reaction was stirred at 0° C. for 30 minutes. 1-Benzyl-4-piperidone(40.0 mL, 220 mmol) was added to the reaction mixture dropwise. Thereaction was warmed to ambient temperature and held with stirring for 1h. The reaction mixture was diluted with diethyl ether (500 mL), washedwith water (2×), then brine. The organic layer was dried (magnesiumsulfate), filtered, and concentrated in vacuo. The residue was dissolvedin methanol (220 mL). Platinum(IV) oxide (600 mg, 2.64 mmol) was addedto the mixture. The reaction vessel was placed on a Parr apparatus,charged with 40 psi of hydrogen gas, and shaken at room temperature for5 h. The reaction mixture was removed from the apparatus, filteredthrough celite, and concentrated. The residue was passed through a shortcolumn of silica gel eluting with ethyl acetate. Fractions wereconcentrated in vacuo. The title compound was obtained as amber oil in90% yield. ¹H NMR (300 MHz, CDCl₃): δ 7.31-7.16 (m, 5H), 3.62 (s, 3H),3.45 (s, 2H), 2.83 (d, J=11.71, 2H), 2.20 (d, J=6.95, 2H), 2.00-1.88 (m,1H), 1.82-1.69 (m, 1H), 1.69-1.59 (m, 2H), 1.38-1.25 (m, 2H). Massspec.: 249.3 (MF)².

Intermediate 2

(±)-Methyl2-(1-benzylpiperialin-4-yl)-3-hydroxy-3-(2-nitrophenyl)propanoate.Diisopropylamine (3.50 mL, 24.9 mmol) was dissolved in tetrahydrofuran(30 mL). The mixture was cooled to −78° C. Butyllithium (2.5 M inpentane, 9.8 mL, 24.5 mmol) was added to the mixture dropwise, and thereaction stirred at −78° C. for 15 min. A solution of methyl2-(1-benzylpiperidin-4-yl)acetate (5.50 g, 22.2 mmol) in THF (8 mL) wasthen added to the mixture dropwise over 20 minutes. The reaction wasstirred at −78° C. for 45 minutes. A solution of 2-nitrobenzaldehyde(3.70 g, 24.5 mmol) in THF (5 mL) was then added to the mixture dropwiseover 15 minutes. The reaction was stirred at −78° C. for 30 minutes andquenched by the addition of saturated aqueous ammonium chloride. Theresulting mixture was warmed to room temperature, extracted with ethylacetate (2×). The combined organics were dried (magnesium sulfate),filtered, and concentrated. Silica gel chromatography afforded thedesired product in 89% yield as light yellow foam. Mass spec.: 399.3(MH)⁺.

Intermediate 3

(±)-3-(1-Benzylpipericiin-4-yl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one.(±)-Methyl2-(1-benzylpiperidin-4-yl)-3-hydroxy-3-(2-nitrophenyl)propanoate (950mg, 2.4 mmol) was dissolved in acetic acid (20 mL). Iron(0) (1.0 g, 17.7mmol) was added to the mixture. The reaction was heated at 85° C. andheld with stirring for 1.5 h. The mixture was cooled to room temperatureand diluted with water (30 mL). The liquid was decanted away from thesolids. The aqueous solution was concentrated in vacuo. The residue wastreated with ethyl acetate (50 mL). The mixture was made basic withaqueous sodium hydroxide. Celite was added to the resulting suspensionto create a slurry which was in turn was filtered. The filtrate layerswere separated. The aqueous layer was extracted with ethyl acetate.Combined organic layers were dried (magnesium sulfate), filtered, andconcentrated in vacuo. The title compound was obtained without furtherpurification as yellow oil in 69% yield. Mass spec.: 335.3 (MH)⁺.

Intermediate 4

3-(1-Benzylpipericlin-4yl)quinolin-2(1H)-one.(±)-3-(1-Benzylpiperidin-4-yl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one(550 mg, 1.6 mmol) was suspended in benzene (10 mL). p-Toluenesulfonicacid monohydrate (370 mg, 1.9 mmol) was added to the mixture. Thereaction was heated to reflux and held there for 1 h. The reactionmixture was concentrated in vacuo. The resulting residue was dissolvedin 10% ethanol/dichloromethane (50 mL) and washed with aqueous sodiumbicarbonate (2×). The organic layer was dried (magnesium sulfate),filtered, and concentrated in vacuo. The residue was triturated withdiethyl ether to give a solid which was filtered, washed with diethylether, and dried in vacuo. The title compound was obtained as off-whitesolid in 63% yield. ¹H NMR (300 MHz, DMSO-d6): δ 11.72 (s, 1H), 7.72 (s,1H), 7.62 (d, ,J=6.95, 1H), 7.47-7.38 (m, 1H), 7.35-7.30 (m, 4H),7.29-7.20 (m, 2H), 7.14 (t, J=7.50, I H), 3.49 (s, 3H), 2.92 (d,j=11.34, 2H), 2.83-2.69 (m, 1H), 2.04 (J=10.61, 2H), 1.78 (d, J=12.08,2H), 1.71-1.47 (m, 2H). Mass spec.: 319.3 (MH)⁺.

Intermediate 5

3-(Piperidin-4-yl)quinolin-2 (1H)-one.3-(1-Benzylpiperidin-4-yl)quinolin-2(1H)-one (1.72 g, 5.40 mmol) wassuspended in methanol (70 mL). A catalytic amount of palladium hydroxide(20% on carbon) was added to the mixture. The reaction vessel was placedon a Parr apparatus and charged with 55 psi of hydrogen. The reactionwas shaken at room temperature for 5 h. The mixture was removed from theapparatus and filtered. The filtrate was concentrated to give the titlecompound as white solid in 90% yield. ¹H NMR (300 MHz, DMSO-d6): δ 7.65(s, 1H), 7.64 (d, ./=10.61, 1H), 7.41 (t, 7.50, 1H), 7.26 (d, J=8.05,1H), 7.13 (t, J=7.32, 1H), 3.02 (d, J=11.71, 2H), 2.82 (t, J=11.89, 2H),2.58 (t, J=11.71, 2H), 1.73 (t, J=11.71, 2H), 1.42 (m, 2H). Mass spec.:229.4 (MH)⁺.

Intermediate 6

2-(((1H-lmidazol-4-yl)methyl)(benzyl)amino)ethanol. A flask was chargedwith 1H-imidazole-4-carbaldehyde (5.0 g, 52 mmol), tetrahydrofuran (75mL), and 2-(benzylamino)ethanol (9.44 g, 62.4 mmol). The reaction wasstirred at room temperature for 1 h. To this was added sodiumtriacetoxyborohydride (13.2 g, 62.4 mmol) in one portion. A significantexotherm was noted. After 10 min, the solution had become a thicksuspension which required occasional agitation by hand. The reaction wasstirred at room temperature overnight. The reaction was concentrated,dissolved in water (100 mL), made basic with an aqueous solution ofpotassium carbonate, and extracted into dichloromethane (3×). Theorganics were dried over potassium carbonate and concentrated. Columnchromatography (5% MeOH/DCM →10% MeOH/DCM→90:10:1 DCM/MeOH/2M ammonia inmethanol) gave 10.2 g (85%) as a viscous oil. Mass spec.: 232.11 (MH)⁺.

Intermediate 7

N-((1H-Imidazol-4-yl)methyl)-N-benzyl-2-chloroethanamine•2HCl. To astirred solution of 2-(((1H-imidazol-4-yl)methyl)(benzyl)amino)ethanol(10.2 g, 44 mmol) in dichloromethane (200 mL) at room temperature wasadded thionyl chloride (12.9 mL, 176 mmol) over 20 min. The resultingheterogeneous, gummy mixture was heated to reflux, occasionallyagitating manually. The reaction was heated at reflux with stirring, for3 h, cooled to room temperature, and stirred at room temperatureovernight. The reaction was concentrated to give a white solid. To thiswas added acetonitrile, and the reaction re-concentrated. The crudeproduct (quant.) was used without purification. Mass spec.: 250.02(MH)⁺.

Intermediate 8

7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine. To a suspension ofN-((1H-imidazol-4-yl)methyl)-N-benzyl-2-chloroethanamine•2HCl (14.23 g,44 mmol) in acetonitrile (250 mL) was added triethylamine (22.1 mL, 159mmol) dropwise via an addition funnel over 30 min. After addition wascomplete, the reaction was slowly warmed to reflux and held there for 2h. The reaction was cooled to room temperature and stirred overnight.The reaction was filtered to remove solids and concentrated. Theresulting risidue was filtered through basic alumina, using 10% MeOH/DCMas eluent. The eluent was concentrated, and the resulting residuepurified by column chromatography (5% MeOH/DCM→10% McOH/DCM) to give2.88 g (31%) as a white crystalline solid. ¹H NMR (CHLOROFORM-d) δ: 7.51(br. s., 1H), 7.26-7.40 (m, 5H), 6.75 (s, 1H), 4.05 (t, J=5.5 Hz, 2H),3.68 (d, J=16.8 Hz, 4H), 2.84 (t, J=5.6 Hz, 2H). ¹³C NMR (CHLOROFORM-d)δ: 137.5, 134.9, 129.1, 128.6, 127.6, 126.2, 122.7, 62.2, 49.8, 49.1,43.0. Mass spec.: 214.08 (MH)⁺.

Intermediate 9

7-Benzyl-5,6,7,8-tetrahydthimidazo[1,5-a]pyrazine-3-carbaldehyde. To asolution of 7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (2.0 g,9.4 mmol) in tetrahydrofuran (15 mL) at −78C was added n-butyllithium(1.6 M in hexanes, 6.5 mL, 10.3 mmol). The reaction was warmed to 0C,stirred for 15 min, recooled to −78C, and treated with dimethylformamide(1.45 mL, 18.8 mmol). The reaction was allowed to warm to 0C, quenchedby addition of saturated ammonium chloride, and concentrated to removemost of the tetrahydrofuran. The reaction was extracted into ethylacetate. The organics were washed with water, then brine, dried overMgSO4, and concentrated. Column chromatography gave 1.80 g (80%) as anoff-white solid. ¹H NMR (CHLOROFORM-d) δ: 9.72 (s, 1H), 7.27-7.43 (m,5H), 7.02 (s, 1H), 4.46 (br. s., 2H), 3.75 (br. s., 4H), 2.92 (br. s.,2H). ¹³C NMR (CHLOROFORM-d) δ: 181.3, 142.8, 129.0, 128.6, 127.8, 127.3,61.9, 49.1, 48.5, 44.7. Mass spec.: 242.03 (MH)⁺.

Intermediate 10

(±)-Diphenyl(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)(phenylamino)methylphosphonate.To a solution of7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carbaldehyde (1.80g, 7.5 mmol) in isopropyl alcohol (15 mL) was added aniline (0.82 mL,9.0 mmol) followed by diphenylphosphite (2.29 mL, 11.9 mmol). Theresulting solution was stirred for 15 min and then allowed to standovernight. In the morning, a precipitate had formed. The precipitate wasfiltered, crushed with a spatula, washed with cold isopropyl alcohol,then ether, air dried, and pumped on high vacuum to give 3.50 g (85%) asa white powder. ¹H MAR (CHLOROFORM-d) δ: 7.22-7.34 (m, 9H), 7.09-7.19(m, 6H), 7.01 (d, J=7.9 Hz, 2H), 6.74-6.80 (m, 4H), 5.42 (d, J=15.6 Hz,1H), 5.07 (br. s., 1H), 4.07-4.21 (m, 2H), 3.60 (s, 3H), 3.46 (d, J=14.3Hz, 1H), 2.74-2.83 (m, 1H), 2.54-2.62 (m, 1H).

Intermediate 11

1-(7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethanone.To a suspension of (±)-diphenyl(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)(phenylamino)methylphosphonate(2.30 g, 4.2 mmol) and7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-5-carbaldehyde(Luo,G., et al, J. Org. Chem. 2006, 5392-5395) (1.21 g, 4.2 mmol) intetrahydrofuran (9.2 mL) and isopropyl alcohol (2.3 mL) was added cesiumcarbonate (1.77 g, 5.4 mmol) in one portion. The reaction was stirred atroom temperature overnight. In the morning, the reaction had stoppedstirring. After getting it stirring again, the reaction was stirred anadditional 2 h. The suspension was cooled to 0C, and treated with 1 NHCl (14 mL) dropwise. The ice bath was removed and the reaction stirredat room. temperature for 2 h. The reaction was diluted with ether andwater. The aqueous was extracted with ether (2×). The ethereal wasconcentrated. Column chromatography (50% EtOAc/Hex→100% EtOAc) gave 525mg (24%) as a foam. ¹H NMR (CHLOROFORM-d) δ: 7.46 (s, 1H), 7.27-7.41 (m,6H), 7.05 (s, 1H), 6.97 (s, 1H), 5.70 (s, 2H), 4.44 (br. s., 2H), 4.39(s, 2H), 3.71 (br. s., 4H), 3.55-3.63 (m, 2H), 2.86 (br. s., 2H), 2.59(s, 3H), 0.89-0.96 (m, 2H), -0.04 (s, 9H). Mass spec.: 516.61 (MH)⁺.

intermediate 12

(±)-1-(7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethox))methyl)-2H-indazol-5-yl)ethanol.To a solution of1-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-2-(2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethanone(400 mg, 0.78 mmol) in ethanol (8 mL) at room temperature was addedsodium borohydride (59 mg, 1.6 mmol). After 30 min, the reaction wascooled to 0C and quenched by the dropwise addition of saturated ammoniumchloride until no further gas evolved. The reaction was concentrated toremove most of the ethanol. The resulting residue was suspended in waterand extracted with ethyl acetate. The organics were washed with brine,dried over MgSO4, and concentrated to give 390 mg (97%) as a white foamwhich was used without purification. Mass spec.: 518.25 (MH)⁺.

Intermediate 13

(±)-1-(7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate. To asolution of 3-(piperidin-4-yl)quinolin-2(1H)-one (668 mg, 2.9 mmol) andtriethylamine (0.41 mL, 2.9 mmol) in dimethylformamide (10 mL) at roomtemperature was added 4-nitrophenylchloroformate (590 mg, 2.9 mmol) intwo portions. After stirring for 30 min, the resulting suspension wasslowly poured into a vigorously stirred flask of water (100 mL). Theresulting solid was collected by filtration, air dried, and pumped onhigh vacuum to give 990 mg (86%) of 4-nitrophenyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate as a lightyellow solid which was used without purification.

To a suspension of(±)-1-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-2-(2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethanol(390 mg, 0.75 mmol) and 4-nitrophenyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (445 mg, 1.1mmol) in tetrahydrofuran (10 mL) at room temperature was added sodiumhydride (95%, 72mg, 3.0 mmol) in one portion. The reaction was stirredat room temperature overnight. The reaction was poured into water andethyl acetate and the layers separated. The organics were washed withsaturated sodium bicarbonate, then brine, dried over magnesium sulfate,and concentrated. Column chromatography (100% EtOAc→10% MeOH/EtOAc) gave365 mg (63%) as a colorless oil. Mass spec.: 772.43 (MH)⁺.

EXAMPLE 1

(±)-1-(7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-7-methyl-1H-indazol-5-yl)ethyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate.(±)-1-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-2-((2-(trimethylsilyDethoxy)methyl)-2H-indazol-5-yl)ethyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (365 mg, 0.47mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 10mL) at room temperature. After 2.5 h, the reaction was concentrated. Thereaction was purified by column chromatography (5% McOH/DCM→7.5%MeOH/DCM). The residue was re-purified by preparative HPLC. Theresulting residue was passed through a shorty column of basic alumina(eluting with 10% McOH/DCM to give 120 mg (40%) as a white foam solid.LC/MS (Analytical HPLC method 1): t_(r)=2.79 min; Mass spec.: 642.35(MH)⁺.

EXAMPLE 2 AND EXAMPLE 3

(1)-1-(7-Ethyl-5,6,7,8-tetrahydroinidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl4-(2-oxo-1,2-dihydroquinoin-3-yl)piperidine-1-carboxylate and2-(7-methyl-1H-indazol-5-yl)-1-(5,6,7,8-tetranydronnidazo[1,5-a]pyrazin-3-yl)ethyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate. A suspensionof(±)-1-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (75 mg, 0.12mmol), palladium (10% on charcoal, 25 mg), and ammonium formate (74 mg,1.2 mmol) in ethanol (3 mL) was heated at reflud for 2 h, occasionallyknocking the sublimed ammonium formate back into the reaction with aspatula. The reaction was cooled, diluted with dichloromethane,filtered, and concentrated. Column chromatography (5% MeOH/DCM→20%MeOH/DCM) gave two fractions. The first to elute was(±)-1-(7-ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (Example 2,8.4 mg, 12%). LC/MS (Analytical HPLC method 2): t_(r)=1.91 min.; Massspec.: 580.31 (MH)⁺. The second to elute was(±)-2-(7-methyl-1H-indazol-5-yl)-1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)ethyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (Example 3,37 mg, 57%). LC/MS (Analytical HPLC method 2): t_(r)=1.80 min; Massspec.: 552.34 (MH)⁺.

EXAMPLE 4

(±)-1-(7-Cyclohexyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate. To asolution of(±)-2-(7-methyl-1H-indazol-5-yl)-1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)ethyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (15 mg, 0.027mmol) and cyclohexanone (5.7 μL, 0.054 mmol) in ethanol (1 mL) at roomtemperature was added sodium cyanoborohydride (3.4 mg, 0.054 mmol).After 5 min, one small drop of acetic acid was added. The reaction wastreated with a second portion of cyclohexanone (5.7 μL, 0.054 mmol),followed by a second portion of sodium cyanoborohydride (3.4 mg, 0.054mmol). After 30 min, the reaction was concentrated and purified bycolumn chromatography (5% →10% MeOH/DCM) gave 11.3 mg (66%) as a whitepowder. LC/MS (Analytical HPLC method 2): t_(r)=1.99 min; Mass spec.:634.36 (MH)⁺.

1. A compound of formula I

where: R¹ is hydrogen, alkyl, cycloalkyl, or (Ar²)alkyl; R² ispiperidinyl substituted with 1 substituent selected from the groupconsisting of

R³ is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; R⁴is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; Ar¹is indazolyl substituted with 0-1 substituents selected from the groupconsisting of halo, alkyl, and haloalkyl; Ar² is phenyl substituted with0-3 substituents selected from the group consisting of halo, alkyl,haloalkyl, alkoxy, and haloalkoxy; and X is O, CH₂, or NH; or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1 whereR¹ is hydrogen, alkyl, cycloalkyl, or (Ar²)alkyl; R² is piperidinylsubstituted with 1 substituent selected from the group consisting of

R³ is hydrogen; R⁴ is hydrogen; Ar¹ is indazolyl substituted with 1alkyl substituent; Ar² is phenyl; and X is O; or a pharmaceuticallyacceptable salt thereof.
 3. A compound of claim 1 where R¹ is hydrogen,ethyl, cyclohexyl, or benzyl; R² is piperidinyl substituted with 1

substituent; R³ is hydrogen; R⁴ is hydrogen; Ar¹ is indazolylsubstituted with 1 methyl substituent; Ar² is phenyl; and X is O; or apharmaceutically acceptable salt thereof.
 4. A compound of claim 1 whereR¹ is hydrogen, ethyl, cyclohexyl, or benzyl.
 5. A compound of claim 1where R² is piperidinyl 4-substituted with 1 substituent selected fromthe group consisting of


6. A compound of claim 1 where Ar¹ is indazolyl substituted with 1 alkylsubstituent.
 7. A compound of claim 1 where Ar² is phenyl.
 8. A compoundof claim I where X is O.
 9. A composition comprising a compound of claim1, or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 10. A method of treating a condition associated withaberrant levels of CORP comprising the administration of atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, to a patient.
 11. The methodof claim 10 where the condition is migraine.